Discussion
Diagnostic assessment of FASD is challenging and relies on a multidisciplinary evaluation approach due to the heterogenic nature of FASD. Additionally, individuals with FASD have a high prevalence of ophthalmological abnormalities.12–14 19 Implementing a complementary ophthalmological diagnostic tool in the diagnostic workup of FASD is warranted.
The results of this study showed significant differences in BCVA, stereoacuity and structural abnormalities when comparing the two groups. These findings indicate that these categories chosen to build the FASD Eye Code are reasonable even in the age group validated in this study. Regarding refraction, the difference in refractive errors between the two groups was not significant. This indicates that category B in the FASD Eye Code might need some adjustment regarding age and cut-off values for refractive errors.
Our results showed that the specificity of the FASD Eye Code was higher than its sensitivity for the cut-off total score of ≥9, which is consistent with the results of Aring et al’s study.20 This indicates that individuals obtaining higher total scores have an increased likelihood of having PAE as the prime aetiological factor behind their ophthalmological abnormalities, although other possible causes should still be investigated in parallel.20 On the other hand, an FASD diagnosis cannot be ruled out when an individual scores lower than 9, which is supported by the fact that about two-thirds of our FASD group scored lower than 9. A cut-off total score of ≥8 resulted in the capture of three more individuals with FASD and one control. In comparison, a cut-off total score of ≥7 instead of ≥9 captured 10 more individuals with FASD and 3 controls. However, the FASD Eye Code should only be used on children being evaluated for suspected FASD, because it is proposed as a complementary diagnostic tool and not as a screening tool, and the overall clinical picture must be taken into consideration. Our ROC curve analysis suggested that a cut-off total score of ≥8 seems to provide reasonable specificity and sensitivity and would likely help in detecting individuals with less severe forms of FASD.
Our results displayed a wide variation in total scores among the study participants, particularly in the FASD group, with the obtained total scores in this group ranging from 4 to 14. This indicates that the severity of ophthalmological involvement in FASD may vary drastically. Regardless of the primary cause behind these findings and whether these individuals reach the cut-off total score or not, abnormalities detected with the FASD Eye Code are important and need clinical management. This study further supports the utility of implementing a complementary ophthalmological diagnostic tool in the FASD diagnostic workup.
The individual in the suspected FASD group who did not receive an FASD diagnosis and was thus excluded from further evaluation had ophthalmological findings that were severe enough to reach a total score of 8. The individual in question had ADHD, which can be associated with ophthalmological abnormalities.28 29 An ROC curve analysis by Aring et al showed an AUC of 0.66 for FASD versus ADHD, which was smaller than the AUC for FASD versus controls,20 and this could explain this case. Furthermore, there is a possibility that this individual would meet the criteria for an FASD diagnosis if evaluated using a different diagnostic system.6 7 10 11
Strabismus, retinal vascular abnormalities and ONH in children with FASD are known to persist into adulthood.15 The mean BCVA shown in our FASD group was similar to the mean BCVA observed in a group of young adults with FASD in a study by Gyllencreutz et al.15 The FASD group evaluated in that study had even been evaluated in childhood (mean age 7.8 years), and a higher mean logMAR BCVA (lower decimal BCVA) than that of our FASD group was observed. Furthermore, our FASD group was more nearsighted than Gyllencreutz et al’s FASD group in childhood but more farsighted than Gyllencreutz’s FASD group in adulthood. This comparison shows that VA and refraction are age-dependent even in individuals with FASD.21 30 31 Aring et al’s FASD group was evaluated using the FASD Eye Code in childhood (aged 4.9–10.5 years) and in young adulthood (aged 19–28 years); these individuals’ total scores were stable into adulthood, and the FASD Eye Code still showed comparable performance despite the age differences.20 Similar performance was displayed in our FASD group, which consisted of older children (aged 9.1–17.8 years).
Some of the typical craniofacial abnormalities associated with FASD that are clinical criteria for FASD have been shown to diminish over time.18 32 In this study, no significant differences in ICD or PFL measures between the two groups were found. This emphasises the need of independent complementary diagnostic tools for FASD.
A previous study by Gyllencreutz et al showed statistically significant thinning of the retinal nerve fibre layer (RNFL) in adults with FASD, visualised on optical coherence tomography (OCT).33 Based on our own clinical experience, some individuals might show significant RNFL thinning on OCT despite not showing any structural abnormalities when examined with a slit-lamp or indirect ophthalmoscopy. Including OCT in the FASD Eye Code could help capture RNFL thinning, and thus increase the sensitivity of this tool. This addition could work in a clinic, but it might be more difficult to apply in studies conducted outside the clinic and in resource-challenged environments, where the size of these devices or their costly nature usually poses a challenge. Recent technical advancements have resulted in handheld OCT devices with comparable performance,34 which might facilitate the future adoption of OCT into the FASD Eye Code.
A previous study by Gyllencreutz et al showed that VPPs are more common in young adults with FASD.16 Increased VPP prevalence—although not statistically significant—was also observed in the FASD group in this study when comparing individuals diagnosed with FASD with controls. Despite missing results from seven individuals with FASD versus one control, four cases of VPPs in children with FASD versus one case in the control group were detected. The difference not being statistically significant could be due to the small sample size analysed or to the fact that one-third of the FASD group had not been evaluated for VPPs. VPPs evaluation could be a sensible addition to the FASD Eye Code. However, this would require having the questions translated and validated in different languages to ensure adequate answers.
The main strengths of our study are that it was conducted using the same methods and diagnostic system used in Aring et al’s study and that our study population was examined by the same multidisciplinary team involved in Aring’s research.20 This team is familiar with FASD and has conducted many studies on this topic.12 14–18 20 33 Furthermore, some potential confounders such as age and sex were taken into consideration in the study design and were minimised by matching individuals with FASD to healthy controls of the same age and sex.
Nevertheless, our study has limitations. The study population is small, which might increase the risk for random errors. All individuals in this study, including the controls, were thoroughly investigated regarding PAE and perinatal and neuropediatric history.21 22 However, our control group could have individuals with undetected PAE. Moreover, our FASD group might not be an accurate representation of the general FASD population: the individuals in our FASD group might have been initially recognised and referred for further investigation due to having more noticeable or severe FASD symptoms.
We have made some clarifications and improvements to the FASD Eye Code protocol in order to avoid misinterpretations.20 In online supplemental file 3, we present the FASD Eye Code 2.0. The results obtained in Aring et al’s study and in this study using the original FASD Eye Code would have been the same regardless of the version of the FASD Eye Code used in the clinical assessment.
In conclusion, our findings emphasise the importance of an ophthalmological evaluation in suspected FASD. The FASD Eye Code showed good diagnostic performance in this study, with a high AUC, and our results suggest that lowering the cut-off total score from 9 to 8 could help in detecting individuals with milder forms of FASD. However, the FASD Eye Code requires further testing on larger FASD groups, preferably of different ethnic backgrounds and corresponding controls, as well as on additional groups with clinical conditions not attributed to PAE.